Abstract

Recent studies suggest that the toxicity of familial amyotrophic
lateral sclerosis mutant Cu, Zn superoxide dismutase (SOD1) arises
from its selective recruitment to mitochondria. Here we demonstrate
that each of 12 different familial ALS-mutant SOD1s with
widely differing biophysical properties are associated with mitochondria
of motoneuronal cells to a much greater extent than
wild-type SOD1, and that this effect may depend on the oxidation
of Cys residues. We demonstrate further that mutant SOD1 proteins
associated with the mitochondria tend to form cross-linked
oligomers and that their presence causes a shift in the redox state
of these organelles and results in impairment of respiratory complexes.
The observation that such a diverse set of mutant SOD1
proteins behave so similarly in mitochondria of motoneuronal cells
and so differently from wild-type SOD1 suggests that this behavior
may explain the toxicity of ALS-mutant SOD1 proteins, which
causes motor neurons to die.